JP4362012B2 - Iontophoresis with current-programmed adjustment - Google Patents

Abstract

The present invention is an apparatus and method that maintains a constant drug delivery rate for an electrotransport delivery system, while the apparent transport efficiency of the system varies, by making adjustments to the output current of the system. More specifically, the constant drug delivery rate is maintained by the regulator of the electrotransport delivery system automatically adjusting the output current to compensate for the varying apparent transport efficiency.

Description

[0001]
TECHNICAL FIELD OF THE INVENTION The present invention relates generally to an electrotransport delivery system (hereinafter "ETS") for delivering a beneficial agent (e.g., drug) to a patient transdermally or transmucosally. . More particularly, the present invention relates to a portable or patient-wearable ETS having an automated delivery regulator that electrically compensates for changes in the apparent transport efficiency of the device to achieve a desired drug delivery rate.
BACKGROUND OF THE INVENTION As used herein, "electrotransport" generally refers to the delivery of a drug (eg, a drug) through a membrane (eg, skin, mucous membrane, or nail). Represents. Drug delivery is induced or facilitated at least in part by applying an electrical potential. For example, beneficial therapeutic agents can be introduced into the animal's (eg, human) systemic circulation by electrotransport delivery through the skin.
[0002]
The electrotransport process has been found useful in transdermal administration of drugs, including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and many other drugs. Perhaps the most common use of electrotransport is to diagnose cystic fibrosis by supplying pilocarpine salt by iontophoresis. Pilocarpine promotes sweating, collects sweat, and analyzes chloride content for disease.
[0003]
Currently known electrotransport systems use at least two electrodes placed in intimate contact with certain parts of the animal's body (eg, skin). The first electrode (referred to as the active or donor electrode) delivers a therapeutic agent (eg, drug or prodrug) into the body by electrotransport. A second electrode (referred to as a counter electrode or return electrode) closes the electrical circuit with the first electrode through the animal's body. An electrical energy source (eg, a battery) supplies current to the body through the electrodes. For example, if the therapeutic agent to be delivered to the body is positively charged (ie, cation), the anode serves as the active electrode, and the cathode serves as the counter electrode to complete the circuit. When the therapeutic agent to be delivered is negatively charged (ie anion), the cathode becomes the donor electrode and the anode becomes the counter electrode.
[0004]
Alternatively, both the anode and cathode can be used to deliver an oppositely charged drug into the body. In this case, both electrodes are considered to be a donor electrode and a counter electrode. For example, the anode can simultaneously serve as a cationic therapeutic agent supply and a “counter” electrode for the cathode. Similarly, the cathode can simultaneously serve as an anionic therapeutic agent delivery into the body and as a “counter” electrode for the anode.
[0005]
In the electrotransport method (also called iontophoresis), which is a widely used electrotransport process, charged ions are transported by electrical induction. In electroosmosis, another type of electrotransport process, the liquid solvent flow from the donor electrode to the counter electrode or the liquid solvent flow from the counter electrode to the donor electrode under the influence of the applied electric field Make it easy to wake up.
[0006]
In still another type of electrotransport process, electroporation, a high voltage pulse is applied to cause temporarily existing pores to form in the biological membrane. A portion of the therapeutic agent is delivered through the skin by passive diffusion due to the concentration difference between the drug concentration in the ETS donor reservoir and the drug concentration in the animal body tissue be able to. In some electrotransport processes, two or more of these processes may occur simultaneously to some extent.
[0007]
Thus, as used herein, the term “electrotransport” includes the electrical of at least one therapeutic agent (whether it is a charged substance, an uncharged substance, or a mixture thereof). The broadest reasonable and possible interpretation is to be given to include induced or increased transport. Furthermore, the load current and the current flowing through the skin are defined as the current flowing between the two electrodes.
[0008]
Electrotransport systems generally require a reservoir or source of a drug or precursor of such drug that is delivered into the body by electrotransport. Examples of reservoirs or sources of drugs (preferably ionizable drugs or ionizable drugs) include the pouch described in Jacobsen, U.S. Pat.No. 4,250,878, or disclosed in U.S. Pat.No. 4,383,529. There are pre-formed gel bodies and the like. Such a reservoir is electrically connected to the anode or cathode of the ETS to provide a fixed or renewable source of one or more desired therapeutic species.
[0009]
Recently, many US patents have been granted patents in the field of electrotransport and it can be seen that there is continuing interest in this form of drug delivery. For example, U.S. Pat.No. 3,991,755 by Vermon et al., U.S. Pat.No. 4,141,359 by Jacobsen et al., U.S. Pat.No. 4,398,545 by Wilson, U.S. Pat.No. 4,250,878 by Jacobsen, U.S. Pat.No. 5,207,752 by Sorenson et al. US Pat. No. 5,213,568 and US Pat. No. 5,498,235 by Flour disclose examples of electrotransport systems and some uses of such electrotransport systems. All of the above patents are incorporated herein by reference.
[0010]
More recently, electrotransport delivery systems have become increasingly smaller, particularly with the development of smaller electrical circuits (eg, integrated circuits) and more powerful lightweight batteries (eg, lithium batteries). The advent of cheap, miniaturized electrical circuits and compact, high-energy batteries means that the entire system can be made small enough to be invisible to the patient's skin under clothing. I mean. This allows the patient to remain fully ambulatory and to perform any normal behavior even when the electrotransport system is delivering drugs.
[0011]
However, the prior art ETS still has some drawbacks, which limits the wider application of ETS equipment. One such drawback is that it is difficult to adjust the rate of drug delivery to ETS users when the apparent transport efficiency of ETS for the drug in use is not constant. ["Apparent transport efficiency" (hereinafter referred to as "ATE") represents a measurement of the amount of drug delivered per unit time by "ETS". More specifically, the ETS ATE for the drug being used is equal to the value obtained by dividing the amount of drug delivered per unit time by the average current output over that time by ETS. In this case, the “average current” is an average current flowing between the two electrodes of the ETS.
[0012]
The ETS ATE for a given drug may vary as a function of time or as a function of other parameters (eg, donor electrode pH level) when a constant drug delivery rate is required to be maintained. For example, in the case of fentanyl-on-demand ETS, it is generally necessary that all doses delivered to the user at the time of application are equal, so that the patient obtains the same release after each administration. If the drug delivery rate is not adjusted properly, a serious situation can occur where the dose is excessive or insufficient. However, under certain conditions, the ATE of fentanyl delivered by ETS appears to vary considerably when delivered by ETS, which makes the fentanyl delivery of prior art ETS unsuccessful.
[0013]
Stabilization of ATE to humans for certain drugs appears to occur quickly and is therefore easy to deliver with conventional ETS technology. For example, several trial clinical studies, including electrical transdermal delivery of metoclopramide, have repeatedly shown that ATE for this drug appears to stabilize within 1 hour of application.
[0014]
However, in certain applications (eg, fentanyl demand supply under certain conditions), the ATE of prior art ETS equipment changes and is within the acceptable range of using prior art ETS equipment. Maintenance of drug delivery rate is impeded.
[0015]
Accordingly, there is a need for an improved ETS that maintains a constant drug delivery rate as the ATE changes.
Summary of the invention The present invention overcomes the above disadvantages of the prior art. The present invention provides an apparatus and method that maintains a constant drug delivery rate for ETS as the ATE changes. More specifically, a constant drug delivery rate is maintained by the ETS regulator of the present invention that automatically adjusts the output current to compensate for changes in ATE.
[0016]
It can be seen that the first task in delivering the desired level of drug using ETS is to obtain an accurate model of the ATE profile that varies with specific parameters. Once an accurate ATE model is obtained, the required average output current profile (ie, average output current that has changed over time) is calculated to maintain a constant drug delivery rate. The present invention automatically adjusts the output current or current application time in certain applications (e.g. on-demand dosing) to maintain the target drug delivery rate for the selected ATE model. Match your profile.
Detailed Disclosure of the Invention 1. Apparent Transportation Efficiency
As a first step in delivering the desired level of drug using ETS, an accurate model of the drug's ATE profile must be obtained.
[0017]
The amount of drug supplied from the ETS and the ATE relative to the ETS is determined primarily by the charge of the ETS, the current density, and the donor electrode formulation. When ATE is evaluated as a function of application time, the kinetics of stabilization can be fairly rapid in some cases (eg, for metoclopramide). In the case of other drugs (eg, for fentanyl electrotransport under certain conditions), ATE may require longer times to stabilize. Various ATE models that require longer time to stabilize are shown in FIGS.
ATE model 1
FIG. 1 is the simplest ATE profile model increasing linearly as a function of time. More specifically, the ATE profile for a particular drug that increases linearly with time (t) is
ATE (t) = ATE ₀ + K _ATE * t Equation (1)
(Where ATE ₀ is the ATE at the start of application time and K _ATE is a proportionality constant). Equation (1) is shown by the line 11 increasing in a constant state in FIG. This means that as time increases, the efficiency of drug delivery (ATE) also increases, so less load current is needed to deliver the same amount of drug.
ATE model 2
In addition to ATE changing as a linear function of time, ATE may be a function of other parameters. For example, in some cases of fentanyl on demand ETS, ATE may vary as a function of the number of doses delivered. Similarly, the pH of the donor electrode (which can change as a function of release time) can change the ATE. Therefore, when ATE changes with donor electrode pH, this relationship is
ATE (pH) = ATE ₀ + K _ATE * pH Formula (2)
Can be expressed as The constant increasing line 21 in FIG. 2 shows ATE as a function of pH level. However, the ATE may be a linearly decreasing function or a non-linear function of pH level. The following is an example of an ATE function having nonlinear characteristics.
ATE model 3
In some cases where fentanyl is delivered transdermally using a direct current of 0.01-0.1 mA / cm ² , it appears that some time is required to stabilize the ATE. For example, according to one pilot clinical study including a specific formulation of fentanyl, 0.1 mA / cm ² current, 2 cm ² electrode area, and application time of 24 hours, ATE at 12 hours is 1 hour It was about 200% of that. Between 12 and 24 hours, the increase was only about 10%.
[0018]
Therefore, from the above study, for some formulations of fentanyl, ATE can be expressed as
ATE = ATE ₀ * (1−exp ^(-KAT2 * ^t) ) Equation (3)
(In the formula, KAT2 represents another proportionality constant). This equation (3) is shown by a curve 31 in FIG. In addition to the exponentially increasing ATE function, the present invention contemplates other non-linear ATE functions.
[0019]
In general, ATE is a function of many parameters such as time, pH level, number of doses applied, and competitive ions. Ie
ATE = f (a, b, c, ...) Equation (4)
This is a general function that may be a linear function or a nonlinear function of a parameter.
[0020]
II. The total amount of drug delivered (AMT) to obtain the desired i _avg is directly proportional to ATE multiplied by the average current (i _avg ). Ie
AMT = ATE * i _avg * K formula (5)
(Where K is a proportionality constant obtained empirically). Equation (5) shows that when ATE and K are known, the desired level of AMT is maintained by appropriately adjusting the current to the desired i _avg . The desired i _avg is also referred to as the desired load current. Equation (5) further shows that i _avg and ATE are inversely proportional to each other in order to keep AMT constant. Thus, to maintain a constant level of supply, i _avg must decrease when ATE is increasing, and i _avg must increase when ATE is decreasing.
[0021]
Thus, an accurate model of the desired i _avg of the drug is required as a second step in delivering the desired level of drug using ETS.
[0022]
For ATE model 1, i _avg must be adjusted using the same proportionality constant. That is,
i _avg (t) = i ₀ −K _ATE * t Equation (6)
(Where i ₀ is the initial average current). The above equation is shown as a linearly decreasing line 13 in FIG. In order for AMT to remain constant over that time, the rate of decrease of i _avg must be equal to the rate of increase of ATE.
[0023]
In the case of ATE model 2, if the correlation between pH and ATE is known, and if the sensor in the donor electrode indicates that the pH has shifted,
i _avg (pH) = i ₀ −K _ATE * pH formula (7)
Thus, i _avg can be adjusted to maintain the supply rate within the performance specifications. A linearly decreasing line 23 in FIG. 2 represents the above equation. Similar to the embodiment for ATE model 1, i _avg (pH) is inversely proportional to ATE (pH) in order to maintain a constant AMT level.
[0024]
In this embodiment, the sensor measures the pH level shift, but in other embodiments contemplated within the scope of the present invention, the sensor further comprises the dose level already supplied by the ETS, the instantaneous current and Any other parameter that helps to generate an appropriate adjustment value for voltage, treated skin resistance, or i _avg can be measured.
[0025]
In the case of ATE model 3, in order to maintain a constant AMT, it is necessary to reduce i _avg as follows.
[0026]
i _avg (t) = i ₀ * exp ^{(-KAT2 * t)} (8)
This is shown as curve 33 in FIG.
[0027]
However, under other specific circumstances, fentanyl ATE can be used if a certain AMT is required.
i _avg (t) = i ₀ * (1−exp ^{(-KAT2 * t)} ) Equation (9)
I _avg needs to be increased, as a function of time.
[0028]
Finally, in the case of a general ATE function as shown in Equation (4), in order to maintain a constant AMT, a desired i _avg function is obtained according to this general function.
[0029]
III. Load current i _L
Once the desired i _avg is determined, ETS is performed to adjust the load current i _L to produce the desired i _avg . A regulator in the ETS generates a load current i _L according to a predetermined load current pattern. FIG. 4 shows a preferred embodiment of such an ETS that includes a power source 51, a regulator 53, a sensor 59, and a pair of electrodes 55 and 57.
[0030]
The external power source 51 is preferably a lightweight portable battery connected to the regulator 53, but may be composed of a number of batteries individually connected to the regulator 53.
[0031]
The regulator 53 receives power from the power source 51 and supplies a load current i _L that flows between the electrodes 55 and 57 in accordance with a predetermined load current pattern. The load current flows from the electrode 55 to the electrode 57 through the treated skin 60. A drug reservoir is attached to one or both of electrodes 55 and 57. The regulator 53 further receives detected information from the sensor 59, but the regulator 53 can operate with or without the sensor 59.
[0032]
In the exemplary embodiment of regulator 53 that supplies load current i _L with respect to ATE model 2 above, sensor 59 determines the pH level of electrode 55. However, sensor 59 can be connected to other devices or skin surfaces to measure dose levels, instantaneous currents and / or voltages, treated skin resistance, or other parameters already supplied by ETS. Can do.
[0033]
In a typical preferred embodiment, the regulator incorporates a microcontroller, microprocessor, other programmable electronic device, or means known to those skilled in the art of electrical circuit design. The desired average load current I _avg is then downloaded from the external processor to the regulator. This embodiment can be used when a patient takes his ETS to a doctor with an ETS programmer. When a doctor prescribes a drug to be administered to a patient using ETS, the doctor downloads the appropriate I _avg function from the ETS programmer to the ETS. The ETS then selects and generates an appropriate load current i _L pattern from the downloaded I _avg . In another embodiment, the pattern of the load current i _L is downloaded directly, so that ETS can skip to the step of calculating the pattern of the load current i _L from the downloaded I _avg .
[0034]
In another exemplary embodiment, the I _avg function is pre-stored in ETS. The patient or doctor selects an appropriate i _avg function from pre-stored functions. In another embodiment, the load current i _L pattern is stored in the ETS, which allows the patient or physician to directly select the appropriate load current i _L pattern.
[0035]
In yet another exemplary embodiment, ETS and internal regulator is implemented with the circuit board or circuit component compatible, each pattern of the load current i _L at this time more kinds first circuit Compatibility is Oite carried out. The patient or doctor can insert a compatible substrate or component appropriate for the particular drug to be administered.
[0036]
Here, the load current pattern will be described in more detail. When the load current i _L is direct current , the generated load current pattern adjusts the load current i _L by changing the level of the load current .
[0037]
In other embodiments, if the load current i _L is a pulse (square wave) current, the generated load current pattern can be obtained by changing the load current i _L by changing the magnitude of the i _L pulse, or i _L Adjust by changing the duty cycle of the pulse . For example, I _avg of 0 to 0.05 mA / cm ² and 10% duty cycle pulse is 0.005 mA / cm ² . The frequency is less than 100 Hz to meet the purpose of this embodiment. To double the above i _avg is to increase the load current i _L to 0-0.1 mA / cm ² while keeping the duty cycle constant at 10%, or to increase the load current i _L to 0-0.05. This is accomplished by doubling the duty cycle to 20% while maintaining mA / cm ² (note that these relationships are approximate). When other modulation current is used, the load current i _L can be changed by changing the waveform. In the case of direct current or pulsed current, the total time of current application can also be adjusted to obtain the desired drug delivery rate (particularly in on-demand delivery applications).
[0038]
In another embodiment, the voltage supplied across electrodes 55 and 57 is controlled by regulator 53 to achieve the desired i _avg . This is because the load voltage and load current i _L between the two electrodes 55 and 57 follow Ohm's law (voltage = current * resistance), so if the sensor knows the resistance of the skin, the load voltage This is possible because the load current is adjusted by adjusting.
[0039]
These methods can be implemented using the approach described above. The current waveform or output voltage (and thus control output current) can be controlled by pre-programming circuit elements (eg, processor or controller) or by changing circuit components or circuit boards.
[0040]
Any drug can be used as long as it is at least partially ionized. The terms “drug” and “agent” are used interchangeably herein and are the broadest and most appropriate interpretations (ie, delivered to the body to produce the desired effect (usually beneficial) Therapeutically active substance that produces a positive effect). For example, the terms “drug” and “drug” include anti-infectives (eg, antibiotics and antivirals), analgesics (eg, fentanyl, safentanil, buprenorphine, and analgesic combinations), anesthetics, anti- Arthritis drugs, anti-asthma drugs (e.g. terbutaline), anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal drugs, antihistamines, anti-inflammatory drugs, antimigraine drugs, antimotion sickness preparations (E.g. scopolamine or ondansetron), antitumor drugs, antiparkinson drugs, antidiarrheals, antipsychotics, antipyretic drugs (including gastrointestinal and urinary), anticholinergics, sympathomimetic drugs, xanthines And derivatives thereof, preparations for cardiovascular diseases (calcium channel blockers such as nifedipine), beta agonists (for example, dobutamine and ritodrine), beta blockers, Arrhythmic drugs, antihypertensive drugs (for example, atenolol), ACE inhibitors (for example, lisinopril), diuretics, vasodilators (including general blood vessels, coronary arteries, peripheral blood vessels, and cerebral blood vessels), central nervous system stimulants, cough / cold Preparations, decongestants, diagnostic agents, hormones (e.g. parathyroid hormone), sleeping pills, immunosuppressants, muscle relaxants, parasympatholytics, parasympathomimetics, prostaglandins, proteins, peptides, psychostimulants, Includes, but is not limited to, therapeutic compounds and molecules from any therapeutic category including sedatives and tranquilizers.
[0041]
The electrotransport device of the present invention includes baclofen, beclomethasone, betamethasone, buspirone, cromolyn sodium, diltiazem, doxazosin, droperidol, encainide, fentanyl, hydrocortisone, indomethacin, ketoprofen, lidocaine, methotrexate, metoclopramide, miconazole piramide, midizolam, More preferably, drugs and / or agents including prazosin, scopolamine, sufentanil, terbutaline, testosterone, tetracaine, and verapamil are provided.
[0042]
The electrotransport device of the present invention preferably further supplies peptides, polypeptides, proteins, and other macromolecules. Such molecules are known in the art to be difficult to deliver transdermally or transmucosally due to their size. For example, such molecules may have a molecular weight in the range of 300 to 40,000 daltons, such as LHRH and its analogs (e.g., buserelin, gosserelin, gonadorelin, nafrelin, and leuprolide), GHRH, GHRF, Insulin, insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36, ie N-[[((s) -4-oxo-2-azetidinyl] carbonyl] -L-histidyl-L-prolinamide, repressin, bottom Pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate), follicile luteoids, α-ANF, growth factor releasing factor (GFRF), β-MSH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor, Asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, Lucicotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, hirulog, hyaluronidase, interferon, interleukin-2, menotropin (e.g., urofotropin (FSH) and LH), oxytocin , Streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analog, ANP, ANP clearance inhibitor, angiotensin II antagonist, antidiuretic hormone agonist, antidiuretic hormone antagonist, bradykinin antagonist, CD4, serase, CSF, enkephalin, FAB fragment, IgE peptide inhibitor, IGF-1, neurotrophic factor, colony stimulating factor, parathyroid hormone and agonist, parathyroid hormone and antagonist, prostaglandin antagonist, pentigetide, protein C, Protein S, renin inhibitors, thymosin alpha-1 antitrypsin (recombinant), and TGF-beta there are such as, but not limited to.
[0043]
While the invention has been described in terms of a preferred form, it will be appreciated by those skilled in the art that various modifications and variations can be made without departing from the spirit and scope of the appended claims.
[Brief description of the drawings]
FIG. 1 is a time line plot of ATE and i _avg for a constant drug delivery rate when ATE is a function that increases linearly with time.
FIG. 2 is a plot of ATE and i _avg versus constant drug delivery rate when ATE is a function that increases linearly with pH level.
FIG. 3 is a time line plot of ATE and i _avg for a constant drug delivery rate when ATE is an exponentially increasing function over time.
FIG. 4 is a schematic configuration diagram of a preferred exemplary embodiment of the regulator.

Claims (14)

An electrotransport device for delivering beneficial drugs,
(a) the first electrode;
(b) a second electrode;
(c) a power source electrically connected to these electrodes;
(d) Regulator for adjusting the power supply
(e) at least one beneficial agent reservoir coupled to the electrode; and
(f) includes compatible circuit boards or circuit components,
The regulator generates a load current based on a predetermined load current pattern stored in the device, determined from an apparent transport efficiency profile predetermined for the device for the drug ; and The load current supplied at this time achieves a desired load current that is inversely proportional to the apparent transport efficiency of the beneficial agent, at which time a constant beneficial agent delivery rate is maintained,
The apparent transport efficiency of the beneficial agent is ATE ₀ * (1-exp ^(-KATE * ^t) ) and the desired average current is i ₀ * exp ^(-KATE * ^t) (where ATE ₀ and i ₀ Are respectively the initial apparent transport efficiency and the initial desired load current, K _ATE is the rate constant, and t is the time)
The load current is a pulse current, the load current is adjusted by adjusting one of the pulse magnitude, time, and duty cycle, and the load current pattern is a compatible circuit board or circuit component Carried out in
Said device. An electrotransport device for delivering a beneficial agent,
(a) the first electrode;
(b) a second electrode;
(c) a power source electrically connected to these electrodes;
(d) a regulator that regulates the power supply; and
(e) at least one beneficial agent reservoir coupled to the electrode;
At which time the regulator generates the load current necessary to produce the desired beneficial agent delivery rate and the desired beneficial agent delivery rate is changed when the apparent transport efficiency changes during delivery of the beneficial agent. In order to maintain, the load current is varied according to a predetermined load current pattern stored in the device, determined from an apparent transport efficiency profile predetermined for the device for the drug ,
a) Whether the apparent transport efficiency of the beneficial agent increases linearly with time and the load current decreases linearly with time,
b) the apparent transport efficiency of the beneficial agent changes non-linearly with time and the load current changes non-linearly with time, or
c) The apparent transport efficiency of the beneficial agent varies with the load current according to the change in the pH level of one or both of the two electrodes,
Electrotransport equipment . The apparatus of claim 2, wherein the load current is direct current and is adjusted to a level of the load current by the regulator . The apparatus of claim 2 , wherein the load current is a pulse current, and any of a pulse magnitude, time, and duty cycle of the current is adjusted by the regulator . The device according to claim 2, wherein a load current pattern is downloaded from the outside. The apparatus of claim 2, wherein the predetermined load current pattern is selectable from a linear function of time, a non-linear function of time, and a function of the pH level of either of the two electrodes. The load current pattern is
(a) i ₀ −K _ATE * t (where i ₀ is the initial load current and K _ATE is a proportional constant);
(b) i ₀ * exp ^(-KATE * ^{t) where} i ₀ is the initial load current, K _ATE is a proportional constant, and t is time;
(c) a function of the pH level of either of the two electrodes;
The device of claim 2, wherein the device is selectable. Load current is
(a) DC changed by changing the level of load current; and
(b) Pulse current altered by changing either the pulse magnitude or duty cycle;
The apparatus of claim 2, wherein 9. Apparatus according to any one of claims 2 to 8, wherein the apparatus is applied using either a microcontroller or a microprocessor. 10. A device according to any one of claims 2 to 9, wherein the device is applied using a compatible circuit board. 11. A device according to any one of claims 2 to 10, wherein the desired beneficial agent delivery rate is kept substantially constant by automatically adjusting the load current as the apparent transport efficiency changes. 12. The device according to any one of claims 2 to 11, wherein the drug is fentanyl. The apparent transport efficiency of the beneficial agent is ATE ₀ + K _ATE * t and the desired load current is i ₀ −K _ATE * t, where ATE ₀ and i ₀ are the initial apparent transport efficiency and 3. The apparatus of claim 2 , wherein the initial load current, t is time, and K _ATE is a proportionality constant. The apparent transport efficiency of the beneficial agent is ATE ₀ * (1-exp ^(-KATE * ^t) ) and the desired load current is i ₀ * exp ^(-KATE * ^t) , where ATE ₀ and i 3. The apparatus of claim 2 , wherein ₀ is the initial apparent transport efficiency and initial load current, respectively, K _ATE is a rate constant, and t is time.